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KRAS Inhibitor Boosts T Cell Production, Shrinks Pancreatic Cancer Tumors

Dr. Ben Stanger from University of Pennsylvania, funded by Sky Foundation was featured in an article on Inside Precision Medicine that discusses how most pancreatic cancers have mutations in the KRAS oncogene, which for the past 30 years has been deemed “undruggable.” But recent advances in chemistry have changed that. New drugs that can antagonize this driver of tumor growth are now being developed.

 

Researchers from the University of Pennsylvania have discovered that a small molecule KRAS-targeted therapy stopped cancer growth or shrank tumors in animal models of pancreatic cancer. They found that the drug inhibits the activity of the most common KRAS mutation in pancreatic cancer and simultaneously boosts T cells mediated immunity. The study was published in Cancer Discovery.

As the name implies, targeted therapies act against specific genes or proteins mutated in tumors. For pancreatic cancer, there are no targeted therapies because there are virtually no known genes that are frequently mutated in the disease for which there are drugs available to target them. An exception is KRAS—one of the first oncogenes to be discovered—and one of the most common. KRAS mutations are found in about 30% of human cancers.

Within the last 10 years drugs targeting KRAS mutations have been developed, particularly against mutant KRAS G12C mutations. The first targeted therapy for KRA sotorasib was approved in 2021 for non-small cell lung cancer with KRAS G12C mutations, but only 1% to 2% of pancreatic cancers express that type of mutation.

 

This drug is just one of a collection of KRAS inhibitors that are being developed by both small biotech firms and large drug companies; we are in the process of evaluating some of these other drugs as well. Of course, these are animal studies, and the real test will come when these agents are given to cancer patients. However, the unprecedented responses we are seeing in our models give us great optimism that one or more of these compounds will have a significant impact in the clinic.

 

The team observed that when treated with the KRAS G12D inhibitor, pancreatic tumors in the mice either shrank or stopped growing. “Almost all of the tumors regressed,” Stanger said. “In the short term, we did not see any resistance; none of them either failed to respond or came back.”

Although this study was not able to assess long-term risk of resistance, Stanger anticipates that resistance will eventually develop to KRAS inhibitors—as with any targeted therapy—as cancers will find a way to develop resistance as they evolve and develop other mutations.

The researchers observed that not only did the tumors shrink after MRTX1133 treatment, but they could measure the depth and duration of their regression. “This depends on the immune system,” said Stanger, adding that the research team found that the drug prompted an increase of T cells in the tumor microenvironment within two to three days.

 

Read the full article on Inside Precision Medicine.